The present invention relates to a novel amorphous form of (S)-1-[N2-(1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline. (S)-1-[N2-(1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline is known under the generic name lisinopril and its novel amorphous form is hereinafter referred to as amorphous lisinopril. Lisinopril has the tendency to readily form into a crystalline shape and no stable amorphous form has previously been reported.
Further, the present invention also relates to the use of amorphous lisinopril in medical treatments, pharmaceutical compositions containing amorphous lisinopril, in particular xe2x80x98fast meltxe2x80x99 formulations, and processes for the preparation of amorphous lisinopril.
The compound (S)-1-[N2-(1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline, having the generic name lisinopril, as well as therapeutically acceptable salts thereof, are described in U.S. Pat. No. 4,374,829 (Merck and Co. Inc.), incorporated herein by reference. In said patent the compound is described in Example 119, and is referred to as N-xcex1-[1(S)-1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline. Lisinopril is a drug on which extensive clinical experience has been obtained. It is currently sold under the trademark ZESTRIL(copyright) or PRINIVIL(copyright).
Lisinopril is a peptidyl dipeptidase inhibitor useful in treating cardiovascular diseases and disorders, such as hypertension and congestive heart failure (CHF) in mammals and especially in man. It inhibits the angiotensin converting enzyme (ACE) that catalyses the conversion of angiotensin I to the vasoconstrictor peptide, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased concentrations of angiotensin II which results in decreased vasopressor activity and reduced aldosterone secretion.
ACE is known to be present in the endothelium and increased ACE activity in diabetic patients which results in the formation of angiotensin II and destruction of bradykinin, potentiates the damage to the endothelium caused by hyperglycaemia. ACE inhibitors, including lisinopril, inhibit the formation of angiotensin II and breakdown of bradykinin and hence ameliorate endothelial dysfunction.
In terms of the pharmacokinetic properties of lisinopril, following oral administration, peak serum concentrations occur within about 7 hours, although there is a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients. On multiple dosing lisinopril has an effective half-life of accumulation of about 12.6 hours. Declining serum concentrations exhibit a prolonged terminal phase, which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25%, with interpatient variability (6-60%) at all doses tested (5-80 mg). Lisinopril does not undergo metabolism and absorbed drug is excreted unchanged entirely in the urine.
It has been reported previously that amorphous forms of certain drugs exhibit distinct dissolution characteristics and in some cases distinct bioavailability patterns compared to the crystalline form (see Konno T, (1990) Chem. Pharm. Bull. 38:2003-2007). The dissolution rate may favor one formulation over another. For some therapeutic indications, one formulation may be favored over another. Similarly one formulation may be more suitable for treating certain patient populations. Therefore it is desirable to have a procedure for making amorphous product or for converting a crystalline form of the drug to the amorphous form.
In addition, it is often desirable to make xe2x80x98fast meltxe2x80x99 tablet formulations of certain drugs.
It has surprisingly been found that the substance lisinopril can be prepared in a stable amorphous form. Moreover, it has been found that amorphous lisinopril possesses far greater solubility than the crystalline form. Such a more soluble form of lisinopril may render the product more suitable to certain formulations where quick solubility is desired, such as xe2x80x98fast meltxe2x80x99 (melt on the tongue type) formulations. It is an object of the present invention to provide amorphous lisinopril. It is a further object of the invention to provide mixtures of amorphous lisinopril with other solid forms of lisinopril, such as crystalline lisinopril. Another object of the present invention is to provide a process for the preparation of amorphous lisinopril, substantially free from other forms of lisinopril.
Additionally it is an object of the present invention to provide pharmaceutical formulations comprising amorphous lisinopril.
Although crystalline lisinopril has been in the public domain for some time now, the Applicants are not aware of any disclosure of amorphous lisinopril having been made and publicly disclosed. Indeed, it was generally regarded that amorphous lisinopril would be difficult to make, particularly in a stable form. Applicants"" previous attempts at crystallization to produce other forms, always generated crystalline hydrates or solvates that quickly took up water reverting to the crystalline form. No amorphous product was ever formed.
Amorphous lisinopril is a non-crystalline, xe2x80x98porous particulatexe2x80x99 form exhibiting advantageous properties, such as being more soluble than crystalline lisinopril. In addition, the amorphous lisinopril particles are glassy in appearance having smooth surfaces with characteristic porous rounded holes with the absence of regular faces present in crystalline materials. Particles can range from small (1-10 xcexcm) to larger particles (500xcexcm) in addition to aggregated particles, which are granular in appearance. The granular shape of the amorphous particles will impart improved flow characteristics and so aid tablet manufacture compared to the needle-like structures found in the crystalline material. ZESTRIL(copyright) is conventionally manufactured using wet granulation and tabletting.
Tablet manufacture by direct compression, as opposed to wet granulation, is prone to segregation of the drug substance from the remaining excipients, leading to a non-uniform mix. This gives rise to tablets of variable drug content. Segregation is exacerbated by wide differences in the particle size of the drug substance and the excipients. The larger particle size of the amorphous lisinopril compared to the crystalline material would be closer to that of the excipients typically used in direct compression formulations and so would minimise segregation. Further, it is well known that amorphous materials posses improved compression characteristics over the crystalline form. For example, commercial grades of lactose are produced by a spray drying technique to introduce some amorphous content which improves the compression force / hardness profile of the excipient (Handbook of Pharmaceutical Excipients, 3rd Edition, A. H. Kibbe, Pharmaceutical Press, p. 276). The particle size and shape of amorphous lisinopril may thus make it more suitable for direct compaction tabletting.
Thus, according to a first aspect of the invention there is provided lisinopril in amorphous form.
There is also provided (S)-1-[N2-(1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline, or a pharmaceutically-acceptable salt thereof in amorphous form.
Amorphous materials do not exhibit the three-dimensional long-range order found in crystalline materials but are structurally more similar to liquids where the arrangement of molecules is random. Amorphous solids are not crystalline and therefore do not give a definitive x-ray diffraction pattern, in addition they do not give rise to a melting point and tend to liquify at some point beyond the glass transition point (Hancock and Zografi, (1997) J. Pharm. Sci., 86:1-12).
The preferred method of differentiating amorphous lisinopril from other crystalline and non-crystalline forms of lisinopril is X-ray powder diffraction (XRPD). The XRPD pattern of pure amorphous lisinopril, as illustrated in FIG. 1, can be seen to lack discernible acute peaks. Thus, amorphous lisinopril, according to the present invention, is characterized in providing an X-ray powder diffraction pattern containing one or more broad diffuse halos having very low counts (i.e. see FIG. 1) in contrast to the sharp diffraction peaks characteristic of crystalline materials (i.e. see FIG. 2). Of course it will be appreciated that a mixture comprising detectable amounts of both crystalline and amorphous lisinopril will exhibit both the characteristic sharp peaks and the diffuse halo(s) on XRPD. This will be evident by an increase in the baseline and also a reduction in crystalline peak intensities.
Thus, according to a further aspect of the invention there is provided amorphous lisinopril characterized in providing an X-ray powder diffraction pattern containing one or more broad diffuse halos, and preferably having very low counts (lacking any discernible peaks).
The term xe2x80x9cbroad diffuse haloxe2x80x9d is the art recognized term for the xe2x80x98humpsxe2x80x99 observed in XRPD (see Klug and Alexander, X-ray diffraction procedures: for polycrystalline and amorphous materials, 2nd edition, 1974, John Wiley and Sons, pp791-792).
In a preferred embodiment the amorphous form is stable.
The term stable as used herein, refers to the tendency to remain substantially in the same physical form for at least a month, preferably at least 6 months, more preferably at least a year, still more preferably at least 3 years, even still more preferably at least 5 years, when stored under ambient conditions (25xc2x0 C./60%RH) without external treatment. As noted above amorphous forms of many compounds often revert to the crystalline form in a relatively short time period (days/weeks rather than months/years). Substantially the same physical form in this context means that at least 70%, preferably at least 80% and more preferably at least 90% of the amorphous form remains. The glass transition point of a compound is a measure of the physical stability to crystallization.
In a preferred embodiment the amorphous lisinopril has in increasing order of preference a glass transition point (Tg), measured by Differential Scanning Calorimetry (DSC) or Thermal Mechanical Analysis (TMA), greater than 70xc2x0 C., 80xc2x0 C., 90xc2x0 C., 100xc2x0 C., 120xc2x0 C., 130xc2x0 C., 140xc2x0 C. and 160xc2x0 C. It is generally regarded that as a rough rule of thumb a Tg of 50xc2x0 C. or greater above the storage temperature should assure reasonable physical stability to crystallization. In a preferred embodiment the amorphous lisinopril according to the invention has, when dry, a glass transition point (Tg) measured by Thermal Mechanical Analysis (TMA) of 100xc2x0 C. or more, more preferably of 120xc2x0 C. or more.
Thus, according to a further aspect of the invention there is provided amorphous lisinopril which is (S)-1-[N2-(1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline, or amorphous salts thereof, providing an X-ray powder diffraction pattern containing one or more broad diffuse halos having very low counts, and possessing, when dry, a glass transition point (Tg) measured by Thermal Mechanical Analysis (TMA) of at least 100xc2x0 C.
Amorphous lisinopril, or the presence of some amorphous lisinopril, can be distinguished from crystalline lisinopril, using X-ray powder diffraction, Raman spectroscopy, solution calorimetry, differential scanning calorimetry, solid state nuclear magnetic resonance spectra (ssNMR) or infra-red spectroscopy. Each of these techniques is well established in the art. Amorphous lisinopril can also be identified based on the morphology of the particles seen under an electron microscope. Furthermore, amorphous lisinopril is much more soluble than crystalline lisinopril, providing another means of discriminating between the crystalline and amorphous lisinopril forms, or detecting an amount of amorphous form within a lisinopril preparation.
As noted above, the preferred method of differentiating amorphous lisinopril from other crystalline and non-crystalline forms of lisinopril is X-ray powder diffraction (XRPD).
Another method of distinguishing physical forms, such as crystalline and amorphous lisinopril, is 13C Solid state NMR spectra (ssNMR) acquired with cross polarization, magic angle spinning and high power proton decoupling. The isotropic chemical shifts (peak positions) measured in solid state NMR spectra are not only a function of the molecule""s atomic connectivity, but also of molecular conformation and inter- and intra-molecular interactions. Thus different peak positions may be observed for different physical forms. For amorphous materials, the dispersion of environments often causes substantially broadened spectra (Nuclear Magnetic resonance Spectroscopy, R K Harris, Longman (1987), p. 155.).
The 13C solid state NMR spectra of amorphous lisinopril, as illustrated in FIG. 4, can be seen to give broadened peaks. Thus, amorphous lisinopril, according to the present invention, is characterised in providing a 13C solid state NMR spectra containing broadened peaks (as in FIG. 4) in contrast to the sharp, well defined peaks characteristic of crystalline materials (as in FIG. 5).
In one embodiment, the amorphous lisinopril of the present invention is substantially free from other forms of lisinopril. Substantially free from other forms of lisinopril shall be understood to mean that amorphous lisinopril contains less than 50%, preferably less than 25%, more preferably less than 10% and still more preferably less than 5% of any other forms of lisinopril, e.g. crystalline lisinopril.
It will be appreciated however, that because of the enhanced solubility property of amorphous lisinopril, mixtures comprising substantially crystalline or other solid forms of lisinopril with amorphous lisinopril will, depending on the amount of amorphous product present, may also possess varying degrees of increased solubility. Such mixtures comprising amorphous lisinopril can be prepared, for example, by mixing amorphous lisinopril prepared according to the present invention with other solid forms of lisinopril, such as crystalline form, prepared according to prior art methods. A mixture might also be prepared if the manufacturing process is incomplete, or incorporates steps that allow or cause amorphous product to be formed.
Thus, the present invention also relates to mixtures comprising amorphous lisinopril in admixture with other solid forms of lisinopril. Such mixtures comprising amorphous lisinopril include for instance mixtures containing a detectable amount of amorphous lisinopril, 1%, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% (by weight), of amorphous lisinopril.
Examples of other solid forms of lisinopril include, but are not limited to, crystalline lisinopril, and other polymorphs.
A detectable amount of amorphous lisinopril is an amount that can be detected using conventional techniques, such as FT-IR, Raman spectroscopy, XRPD, TMA, DSC and the like.
Numerous techniques can be employed to detect a particular form of a compound within a mixture. The limits of detection of a particular form in admixture with another form, i.e. crystalline in amorphous or vice versa, is as follows: by XRPD it is reported to be approximately 5% according to Hancock and Zografi (J. Pharm. Sci., 86:1-12, 1997) and approximately 2.0% according to Surana and Suryanarayanan (Powder Diffraction, 15:2-6, 2000). The limits of detection by solution calorimetry is reported to be approximately 1% according Hogan and Buckton (International Journal of Pharmaceutics, 207:57-64, 2000). The limits of detection by solid state NMR is reported to be approximately 5-10% according to Saindonet al., (Pharmaceutical Research, 10:197-203,1993). The limits of detection by near infra red spectroscopy is reported to be approximately 2-5% according to Blanco and Villar (Analyst, 125:2311-2314, 2000). The limits of detection by Modulated Differential Scanning Calorimetry (MDSC) is reported to be approximately 6% according to Saklatvala et al., (International Journal of Pharmaceutics, 192: 55-62, 1999). The limits of detection by FTRaman spectroscopy is reported to be approximately 2% according to Taylor and Zografi (Pharm. Res. 15:755-761, 1998).
Amorphous lisinopril can be prepared by precipitation. Other ways of making 15 amorphous product include: spray drying, freeze drying (lyophilisation), melt precipitation, vapour condensation, crash cooling, from supercritical fluids e.g. using Solution Enhanced Dispersion by Supercritical fluids (SEDS), Rapid Expansion of Supercritical Solution (RESS) processes etc, co-precipitation with suitable excipients (these include sugars, acids, polymers, insoluble or enteric polymers, surfactants) to form solid dispersions, molecular dispersions, co-precipitates or co-evaporates by melting or fusion, or from solvents, including supercritical solvents.
The preferred method of preparing amorphous lisinopril is by precipitation using an anti-solvent. Thus, amorphous lisinopril may be prepared by dissolving any form of lisinopril in a suitable solvent, such as for instance water or methanol, followed either by (i) precipitation via addition of a suitable antisolvent which is miscible with the first solvent, such as for example acetone when the first solvent is methanol, or (ii) addition of an immiscible antisolvent, such as for example toluene or chlorobenzene when the first solvent is water, and azeotroping to allow precipitation of amorphous lisinopril.
According to one aspect of the invention there is provided a process for the preparation of amorphous lisinopril comprising the steps of:
a) dissolving or suspending lisinopril of any form, or a mixture of lisinopril of any form in a suitable solvent;
b) adding an antisolvent to precipitate out amorphous lisinopril; and,
c) isolating the amorphous lisinopril thus obtained.
In one embodiment the solvent and antisolvent are immiscible and precipitation of the amorphous product in step b) is effected following evaporation of the immiscible solution.
Thus, the process comprises the steps of:
a) dissolving or suspending lisinopril of any form, or a mixture of lisinopril of any form in a suitable solvent;
b) adding an antisolvent which is immiscible with the solvent used in step a);
c) azeotroping to precipitate out amorphous lisinopril; and,
d) isolating the amorphous lisinopril thus obtained.
By the term xe2x80x98any formxe2x80x99 we include, solvated and desolvated forms, crystalline forms and other non-crystalline forms.
In one embodiment the lisinopril is dissolved in the solvent in dehydrated form. In such instances, it is preferred that the dehydrated lisinopril is added to the solvent before the lisinopril has had a chance to rehydrate. It is preferred therefore, that the dehydrated lisinopril is prepared by heating a hydrated form for a suitable length of time and the xe2x80x98still hotxe2x80x99 dehydrate is added directly to the solvent mixture. Equally, in an alternate embodiment, the solvent can be added to the lisinopril dehydrate.
The inventors have found that it is not necessary to dehydrate lisinopril dihydrate in every case. However, if hydrated lisinopril is dissolved in water as the solvent it is preferred that non-polar antisolvents are used. When using dehydrated lisinopril it is preferred that polar antisolvents are used, however non-polar antisolvents can also be used.
It is preferred that the temperature of the mixture during mixing with the antisolvent is 0 to +50xc2x0 C., most preferably +20xc2x0 C. to 40xc2x0 C., and for the antisolvent to be at ambient temperature before mixing. It is preferred to add the antisolvent to the lisinopril solvent solution. The antisolvent may be added continuously or discontinuously, preferably discontinuously in two or more aliquots over a period of up to, but not limited to 8 hours. The amount of antisolvent should be such that the concentration of lisinopril in the resulting mixture is higher than the solubility. The preferred ratio of antisolvent to lisinopril solvent solution should be in the range of 5:1 to 10: I by volume. The water content in the final mixture should preferably be below 10% by volume. Mixing, e.g. agitation or stirring, is preferable both during the dissolving step and the precipitation step. The precipitation should continue for a period to ensure that amorphous product formation is as complete as possible, e.g. up to 15 hours, preferably, 1-8 hours.
The amorphous product may be separated from the solution, e.g. by filtration or centrifugation, followed by washing with a wash solution, preferably a solvent in which amorphous lisinopril has a very low solubility. The amorphous product can be dried to a constant weight, e.g. at +30xc2x0 C. to +50xc2x0 C., preferably at reduced pressure, for, e.g. 10 to 48 hours.
For storage, the amorphous product is preferably kept at 25xc2x0 C., 60%RH (ambient conditions) having a water content up to about 30% (for relative humidities in the range 40% RH-80% RH). In a preferred embodiment the water content is from between about 5% and 20%, more preferably between about 7% and 18%.
The invention is therefore also directed to a method of enhancing the bioavailability of lisinopril, particularly crystalline lisinopril dihydrate, comprising admixing said lisinopril with amorphous lisinopril. Alternatively, the method comprises converting any amount of lisinopril, particularly crystalline lisinopril, to amorphous lisinopril.
In a further aspect, the invention provides a compound obtainable by a process or method as described above.
xe2x80x98Zestrilxe2x80x99 has received regulatory approval for use in the following indications:
Hypertension
xe2x80x98Zestrilxe2x80x99 is indicated in the treatment of essential hypertension and in renovascular hypertension. It may be used alone or concomitantly with other classes of antihypertensive agents.
Congestive Heart Failure
xe2x80x98Zestrilxe2x80x99 is indicated in the management of congestive heart failure as an adjunctive treatment with diuretics and, where appropriate, digitalis. High doses reduce the risk of the combined outcomes of mortality and hospitalization.
Acute Myocardial Infarction
xe2x80x98Zestrilxe2x80x99 is indicated for the treatment of haemodynamically stable patients within 24 hours of an acute myocardial infarction, to prevent the subsequent development of left ventricular dysfunction or heart failure and to improve survival. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers.
Renal And Retinal Complications of Diabetes Mellitus
In normotensive insulin-dependent and hypertensive non-insulin-dependent diabetes mellitus patients who have incipient nephropathy characterised by microalbuminuria, xe2x80x98Zestrilxe2x80x99 reduces urinary albumin excretion rate. xe2x80x98Zestrilxe2x80x99 reduces the risk of progression of retinopathy in normotensive insulin-dependent diabetes mellitus patients.
According to the invention there is further provided a pharmaceutical composition comprising amorphous lisinopril, as active ingredient, in association with a pharmaceutically acceptable carrier, diluent or excipient and optionally other therapeutic ingredients. Compositions comprising other therapeutic ingredients are especially of interest in the treatment of hypertension, congestive heart failure, acute myocardial infarction and in renal and retinal complications of diabetes mellitus.
The invention also provides the use of amorphous lisinopril in the manufacture of a medicament for use in the treatment of a cardiovascular related condition, and in particular, a method of treating a hypertensive or congestive heart failure condition which method comprises administering to a subject suffering from said condition a therapeutically effective amount of amorphous lisinopril or a product comprising amorphous lisinopril. In a further embodiment a therapeutically effective amount of a composition comprising amorphous lisinopril is administered to the subject.
The invention also provides amorphous lisinopril for use in treating hypertension, congestive heart failure, acute myocardial infarction and in renal and retinal complications of diabetes mellitus.
The invention also provides the use of amorphous lisinopril in treating hypertension, congestive heart failure, acute myocardial infarction and in renal and retinal complications of diabetes mellitus.
Any suitable route of administration may be employed for providing the patient with an effective dosage of drug comprising amorphous lisinopril according to the invention. For example, peroral or parenteral formulations and the like may be employed. Dosage forms include capsules, tablets, dispersions, suspensions and the like, e.g. enteric-coated capsules and/or tablets, capsules and/or tablets containing enteric-coated pellets of lisinopril. In all dosage forms amorphous lisinopril can be admixtured with other suitable constituents. The preferred route of administration is peroral using fast melt tablets.
The compositions of the invention comprise the compound of the invention. The compositions may be conveniently presented in unit dosage forms, and prepared by any methods known in the art of pharmacy.
In view of the enhanced solubility that amorphous lisinopril has compared to crystalline lisinopril, compositions wherein some, but preferably a substantial amount, of the total amount of the lisinopril is amorphous (i.e.  greater than 20%), can be prepared as a xe2x80x98fast meltxe2x80x99 tablet and/or formulation.
A fast melt tablet is defined as a tablet dosage form for oral use that disintegrates in the mouth within approximately one minute. Chewing or water is not needed for disintegration. Should the drug and tablet excipients be sufficiently soluble, the tablet dissolves to a complete solution before the patient swallows.
Several advantages of fast melt tablets over conventional oral tablets and liquids may exist. Patient compliance may improve because of ease of swallowing, lack of need for water, and taste-masking and improved accuracy of dosage. Patient populations that may benefit the most include geriatric patients, paediatric patients and patient who cannot swallow or have difficulty in swallowing. A fast melt tablet would also benefit patients with congestive heart failure who tend to retain fluid, and therefore are treated with fluid intake restriction. The fluid used to take their medications are included in the amount of fluid that they are prescribed per day (which may be as little as 500 ml), so a fast melt tablet that can be taken without fluid would benefit these patients.
Fast melt tablets are manufactured by a variety of tablet technologies including wet granulation, direct compression and freeze-drying (see for example: Corveleyn and Remon, International Journal of Pharmaceutics, (1997) 152: 215-225).
For a general review on fast melt technology please consult, Habib et al., (Critical Reviews in Therapeutic Drug Carrier Systems, 17(1):61-72, 2000).
According to a further aspect of the invention there is provided a fast melt tablet formulation comprising amorphous lisinopril.
Crystalline lisinopril dihydrate is soluble in water and should go into solution in the gastrointestinal tract rapidly after ingestion. This is demonstrated by the dissolution of the current marketed Zestril(copyright) tablets in which typically greater than 90% of the dose is dissolved within 15 minutes. Once in solution, absorption is limited by the physicochemical characteristics of the compound, its ability to cross the gastrointestinal mucosa and enter into the blood stream and transit time of the gut. A form that would go into solution more rapidly would only affect the first step however. Thus, despite the enhanced solubility that a lisinopril formulation comprising amorphous form would likely have, because solubility is not a limiting step in the rate and extent of absorption of lisinopril, it is unlikely that this would affect the bioavailability or the clinical benefits of lisinopril.
In the practice of the invention, the most suitable route of administration as well as the magnitude of a therapeutic dose of amorphous lisinopril in any given case will depend on the nature and severity of the disease to be treated. The dose, and dose frequency, may also vary according to the age, body weight, and response of the individual patient.
In general, a suitable oral dosage form may cover a dose range from 0.5 mg to 150 mg total daily dose, administered in one single dose or equally divided doses. A preferred dosage range is from I mg to 60 mg.
Combination therapies comprising amorphous lisinopril and other active ingredients in separate dosage forms, or in one fixed dosage form, may also be used. Examples of such active ingredients include anti-bacterial compounds, non-steroidal anti-inflammatory agents, antacid agents, alginates, prokinetic agents, other antihypertensive agents, diuretics, digitalis, thrombolytics, aspirin and beta-blockers.